Butyrophenone compounds

ABSTRACT

Butyrophenone compounds having excellent psychotropic activities represented by the formula: ##STR1## wherein R 1  is a halogen atom, R 2  is a lower alkyl group, and Z is a group of either one of the formulae: ##STR2## (wherein the dotted line indicates the optional presence of an additional single bond linkage, R 3  is a hydrogen atom or a hydroxyl group but only when said additional single bond linkage is not present and R 4  is a hydrogen atom or a phenyl or benzyl group optionally substituted with one or two substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy and trifluoromethyl on the benzene ring (except monohalophenyl)), ##STR3## (wherein the dotted line indicates the optional presence of an additional single bond linkage, R 5  is a hydrogen atom or a lower alkyl group and R 6  and R 7  are each a hydrogen atom, a halogen atom or a lower alkyl group), ##STR4## (wherein R 8  is a hydrogen atom or a lower alkyl group and R 9  is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group), ##STR5## (wherein R 10  is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group), or ##STR6##

This application is a divisional, of copending application Ser. No.568,819, filed on Apr. 17, 1975 now U.S. Pat. No. 4,039,670.

The present invention relates to novel butyrophenone compounds, topharmaceutical compositions containing them, and to processes for theproduction thereof.

The said novel butyrophenone compounds are representable by the formula:##STR7## wherein R¹ is a halogen atom, R² is a lower alkyl group and Zis a group of either one of the formulae: ##STR8## (wherein the dottedline indicates the optional presence of an additional single bondlinkage, R³ is a hydrogen atom or a hydroxyl group but is not present incase of the dotted line indicating the presence of an additional singlebond linkage being present and R⁴ is a hydrogen atom or a phenyl orbenzyl group optionally substituted with one or two substituentsselected from the group consisting of halogen, lower alkyl, lower alkoxyand trifluoromethyl on the benzene ring (except monohalophenyl)),##STR9## (wherein the dotted line indicates the optional presence of anadditional single bond linkage, R⁵ is a hydrogen atom or a lower alkylgroup and R⁶ and R⁷ are each a hydrogen atom, a halogen atom or a loweralkyl group), ##STR10## (wherein R⁸ is a hydrogen atom or a lower alkylgroup and R⁹ is a hydrogen atom, a halogen atom, a lower alkyl group ora lower alkoxy group), ##STR11## (wherein R¹⁰ is a hydrogen atom, ahalogen atom, a lower alkyl group, a lower alkoxy group or atrifluoromethyl group), and ##STR12##

In the significances as defined above, "lower alkyl" and "lower alkoxy"include groups having one to about four carbon atoms and may be ofstraight or branched chain structure. Examples thereof are methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy. The term"halogen" includes fluorine, chlorine, bromine and iodine.

With respect to the symbol R⁴, it may be monosubstituted phenyl such aslower alkylphenyl, lower alkoxyphenyl or trifluoromethylphenyl,monosubstituted benzyl such as halobenzyl, lower alkylbenzyl, loweralkoxybenzyl or trifluoromethylbenzyl, disubstituted phenyl such asdihalophenyl, lower alkyl-halophenyl, lower alkoxy-halophenyl,halo-trifluoromethylphenyl, lower alkyl-lower alkoxyphenyl, loweralkyl-trifluoromethylphenyl, lower alkoxy-trifluoromethylphenyl,di(lower)alkylphenyl, di(lower)alkoxyphenyl or ditrifluoromethylphenyl,or disubstituted benzyl such as dihalobenzyl, lower alkyl-halobenzyl,lower alkoxy-halobenzyl, halo-trifluoromethylbenzyl, lower alkyl-loweralkoxybenzyl, lower alkyl-trifluoromethylbenzyl, loweralkoxy-trifluoromethylbenzyl, di(lower)alkylbenzyl,di(lower)alkoxybenzyl or ditrifluoromethylbenzyl.

The preferred compounds are, with respect to formula [I], those in whichR¹ is fluorine and R² is methyl.

The butyrophenone compounds [I] in the free base or salt form showvarious pharmacological activities, and their excellent central nervoussystem depressing activity is particularly notable. Thus, they areuseful as medicines such as neuroleptics and analgesics.

In British Patent 1,141,664, there are described the butyrophenonecompounds of the general formula: ##STR13## (wherein Ar is halophenyland Ar' is dihalophenyl or lower alkyl-halophenyl), which are useful ascentral nervous system depressants. In this patent, the compound of theformula: ##STR14## is the only compound as specifically disclosed.

It has now unexpectedly been found that the butyrophenone compounds [I],i.e. those of the formula [A] but having a group of the formula: -Z(wherein Z is as defined above) instead of the4-halophenyl-4-hydroxyl-substituted piperidino group, have a moreexcellent central nervous system depressing activity than that of thecompounds [A] themselves. For instance, the anti-apomorphine activity ofthe butyrophenone compounds [I] in rats is greater than that of thecompound [B].

Accordingly, an object of the present invention is to provide novelbutyrophenone compounds [I] having a central nervous system depressingactivity. Another object of this invention is to provide a process forproducing the butyrophenone compounds [I]. These and other objects willbe apparent to those skilled in the art to which the present inventionpertains from the foregoing and subsequent descriptions.

According to the present invention, the butyrophenone compounds [I] canbe prepared by reacting a compound of the formula: ##STR15## wherein R¹and R² are each as defined above, X is a reactive ester residuederivable from an alcoholic group such as halogen (e.g. chlorine,bromine), arylsulfonyloxy (e.g. benzenesulfonyloxy, toluenesulfonyloxy)or alkylsulfonyloxy (e.g. methanesulfonyloxy) and B is a free orprotected keto group (e.g. keto, ethylenedioxy, ethylenedithio) with acompound of the formula:

    H--Z                                                       [III]

wherein Z is as defined above to give a compound of the formula:##STR16## wherein R¹, R², B and Z are each as defined above, optionallyfollowed by hydrolysis of the latter.

The condensation reaction of the compound [II] with the compound [III]in the free base or salt form is usually carried out in an inert solventsuch as an aromatic hydrocarbon (e.g. benzene, toluene, xylene), anamide (e.g. dimethylformamide, dimethylacetamide), an ether (e.g.dioxane, tetrahydrofuran), an alcohol (e.g. ethanol, n-propanol,butanol, amyl alcohol), an alkanone (e.g. acetone, butanone,methylisobutylketone) or dimethylsulfoxide at a temperature within therange of room temperature to the boiling point of the solvent.Preferably, there may be used a basic substance such as an alkalicarbonate (e.g. sodium carbonate, potassium carbonate), an alkalihydrogen carbonate (e.g. sodium hydrogen carbonate, potassium hydrogencarbonate), an alkali hydroxide (e.g. sodium hydroxide, potassiumhydroxide) or an organic amine (e.g. pyridine, triethylamine) as an acidbinding agent. There may be also used a small amount of a reactionaccelerating agent such as potassium iodide.

The hydrolysis can be carried out by a conventional acid hydrolyzingprocedure. For instance, it can be accomplished by treating the compound[IV] with an acidic substance such as a mineral acid (e.g. hydrochloricacid, sulfuric acid, phosphoric acid), an organic acid (e.g. oxalicacid, tartaric acid) or an acidic ion exchange resin in water or analkanol (e.g. methanol, ethanol, propanol), usually under a mildcondition, e.g. at room temperature. Further, it may be accelerated byelevation of the temperature.

Specific examples of the butyrophenone compound [I] are as follows:

1-[γ-(2-Methyl-4-fluorobenzoyl)propyl]-4(3-trifluoromethylphenyl)-4-hydroxypiperidine;

8-[γ-(2-Methyl-4-fluorobenzoyl)propyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decane;

1-[γ-(2-Methyl-4-fluorobenzoyl)propyl]-4-(2-keto-1-benzimidazolinyl)piperidine;

1-[γ-(2-Methyl-4-fluorobenzoyl)propyl]-4-(2-keto-1-benzimidazolinyl)-1,2,3,6-tetrahydropyridine;

1-[γ-(2-methyl-4-fluorobenzoyl)propyl]-4-(2-methoxyphenyl)piperazine;

1-[γ-(2-Methyl-4-fluorobenzoyl)propyl]-4-benzyl-4-hydroxypiperidine;

1-[γ-(2-Methyl-4-fluorobenzoyl)propyl]-4-(4-chlorobenzyl)-4-hydroxypiperidine;

N-[γ-(2-Methyl-4-fluorobenzoyl)propyl]-morpholine;

1-[γ-(2-Methyl-4-chlorobenzoyl)propyl]-4-(3-trifluoromethylphenyl)-4-hydroxypiperidine;

8-[γ-(2-Methyl-4-chlorobenzoyl)propyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decane;

1-[γ-(2-Methyl-4-fluorobenzoyl)propyl]-4-(3-trifluoromethyl-4-chlorophenyl)-4-hydroxypiperidine;

1-[γ-(2-Methyl-4-fluorobenzoyl)propyl]-4-(3,4-dichlorophenyl)-4-hydroxypiperidine;

1-[γ-(2-Methyl-4-fluorobenzoyl)propyl]-4-(3-chloro-4-methylphenyl)-4-hydroxypiperidine,etc.

These butyrophenone compounds [I] in the free base form can be convertedinto their pharmaceutically acceptable salts such as acid addition saltsor quaternary ammonium salts by treatment with mineral acids (e.g.hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid),organic acids (e.g. acetic acid, citric acid, oxalic acid, lactic acid,succinic acid, tartaric acid, cinnamic acid, ascorbic acid), alkylhalides, aralkyl halides, aromatic sulfonates or the like.

The pharmacological evaluation in animal tests has demonstrated that thebutyrophenone compounds [I] show a variety of depressing activities onthe central nervous system and are useful as medicines such asneuroleptics or analgesics. For instance, they exhibit ananti-apomorphine activity in rats greater than that of Chlorpromazine orthe above mentioned compound [B].

Each of the butyrophenone compounds [I] may be brought into a formsuitable for administration according to a method known per se.

For the preparation of pharmaceutical compositions, they may be mixedwith carriers of diluents such as water, sesame oil, calcium phosphate,starch, talcum, casein, magnesium stearate, methyl cellulose,polyglycols, tragacanth and the like, sometimes together withstabilizers and/or emulsifying agents.

The resulting mixture may be processed in accordance with conventionalprocedures to tablets, capsules, pills, ampoules and the like. The usualoral dosage is 1-200 mg per os daily.

Practical and presently preferred embodiments of the present inventionare illustratively shown in the following Examples, which are notintended to limit the scope of the invention thereto.

EXAMPLE 1

A mixture of 3 g of4-chloro-1-(2-methyl-4-fluorophenyl)-1,1-ethylenedioxybutane, 2.3 g of4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decane, 1.4 g of anhydrouspotassium carbonate, 0.05 g of potassium iodide and 30 ml ofdimethylformamide was refluxed for 3 hours. The resulting mixture waspoured into ice water. The precipitated crystals were collected byfiltration and washed with water to give8-[4-(2-methyl-4-fluorophenyl)-4,4-ethylenedioxybutyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decaneas crude crystals (5 g).

A mixture of 5 g of the crude crystals, 70 ml of methanol, 21 ml ofwater and 11 ml of concentrated hydrochloric acid was refluxed for 50minutes. The resulting mixture was concentrated in vacuo. The residualoil was diluted with water, made alkaline with 28% aqueous ammonia andextracted with chloroform. The extract was washed with water, dried overanhydrous sodium sulfate and concentrated in vacuo to give8-[γ-(2-methyl-4-fluorobenzoyl)propyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decane,melting at about 179.5°-181.5° C.

EXAMPLE 2

A mixture of 3 g of4-chloro-1-(2-methyl-4-fluorophenyl)-1,1-ethylenedioxybutane, 2.5 g of4-(3-trifluoromethylphenyl)-4-hydroxypiperidine, 1.4 g of anhydrouspotassium carbonate, 0.05 g of potassium iodide and 30 ml ofdimethylformamide was refluxed for 3 hours. The resulting mixture waspoured into ice water and was extracted with ethyl acetate. The extractwas washed with water, dried over anhydrous sodium sulfate andconcentrated in vacuo. To the residual oil were added 60 ml of methanol,21 ml of water and 10.5 ml of concentrated hydrochloric acid. Themixture was refluxed for 50 minutes and concentrated in vacuo. Theresidual oil was made alkaline with 28% aqueous ammonia and extractedwith ethyl acetate. The extract was washed with water, dried overanhydrous sodium sulfate and concentrated. The residual solid wasrecrystallized from isopropyl ether to give1-[γ-(2-methyl-4-fluorobenzoyl)-propyl]-4-(3-trifluoromethylphenyl)-4-hydroxypiperidine,melting at about 63.5°-64.5° C.

What is claimed is:
 1. 1-[γ-(2-Loweralkyl-4-halobenzoyl)propyl]-4-(3-trifluoromethylphenyl)-4-hydroxypiperidine,or a pharmaceutically acceptable acid addition salt thereof. 2.1-[γ-(2-Methyl-4-fluorobenzoyl)propyl]-4-(3-trifluoromethylphenyl)-4-hydroxypiperidine,or a pharmaceutically acceptable acid addition salt thereof.
 3. Aneuroleptic or analgesic composition comprising an effective neurolepticor analgesic amount of the compound of claim 1 or a pharmaceuticallyacceptable acid addition salt thereof, and at least one pharmaceuticallyacceptable diluent or carrier.
 4. A neuroleptic or analgesic compositioncomprising an effective neuroleptic or analgesic amount of the compoundof claim 2 or a pharmaceutically acceptable acid addition salt thereof,and at least one pharmaceutically acceptable diluent or carrier.